Levodopa Positively Affects Neovascular Age-Related Macular Degeneration

Abstract

Background: Age-related macular degeneration (AMD) is a common cause of blindness worldwide. Neovascular AMD (nAMD) is an advanced form of the disease, in which excess vascular endothelial growth factor (VEGF) induces growth of new blood vessels that leak fluid, accounting for 90% of vision loss in AMD. Dysfunction of the retinal pigment epithelium likely initiates AMD. Retinal pigment epithelial cells express a G protein-coupled receptor, GPR143, which downregulates VEGF in response to levodopa. Anti-VEGF therapy effectively treats nAMD, suggesting that excessive VEGF activity drives the pathology.

Methods: In an open-label pilot study, in patients with newly diagnosed nAMD and naïve to anti-VEGF injections (Cohort-1), the effects of carbidopa-levodopa on vision and anatomic outcomes were evaluated for 4 weeks. Then patients were followed 5 months further with ascending levodopa doses. Patients previously treated with anti-VEGF injection therapy (Cohort-2) were also treated with ascending levodopa doses and evaluated for 6 months.

Results: Levodopa was safe, well tolerated, and delayed anti-VEGF injection therapy while improving visual outcomes. In the first month, retinal fluid decreased by 29% (P = .02, n = 12) without anti-VEGF treatment. Through 6 months the decrease in retinal fluid was sustained, with a mean frequency of 0.38 injections/month. At month 6, mean visual acuity improved by 4.7 letters in Cohort-1 (P = .004, n = 15) and by 4.8 letters in Cohort-2 (P = .02, n = 11). Additionally, there was a 52% reduction in the need for anti-VEGF injections in Cohort-2 (P = .002).

Conclusions: Our findings suggest efficacy and support the pharmacological targeting of GPR143 with levodopa for the treatment of nAMD in future studies.

Keywords: Age-related macular degeneration (AMD); Carbidopa-levodopa; GPR143; L-DOPA; Neovascular AMD; Prospective study; Retinal pigment epithelium; Wet AMD; nAMD.

Figure 1

Changes from baseline in best-corrected visual acuity (BCVA), central retinal thickness (CRT), and retinal fluid in patients naïve to intravitreal anti-vascular endothelial growth factor therapy (Cohort 1). (A) Mean change from baseline in BCVA ± SE during a 1-month period of levodopa treatment and for comparison, the reported changes in visual acuity adapted from a multicenter, 24-month, sham-controlled study in patients receiving intravitreal injections of ranibizumab (0.3 mg or 0.5 mg). Starting from a baseline mean of 43.4 letters (20/40), at week 1, BCVA increased by 2.9 letters, P = .03; and at week 4, BCVA increased by 5.0 letters with levodopa treatment, P = .03. (B) Mean change from baseline in CRT ± SE over time, CRT decreased by 4.8 μm, P = .02. Wilcoxon-matched pairs signed rank analyses were used to assess changes in BCVA, and paired-sample t tests were used for changes in CRT. (C) Mean percentage change from baseline in retinal fluid ± SE at 1 and 4 weeks. Mean retinal fluid decreased 13% by week 1, P = .07 and by 29% at week 4 (P = .01; 95% CI, −50.3% to −8.2%). To evaluate percentage change in retinal fluid at weeks 1 and 4, from a theoretical mean of no observed change (retinal fluid = 0.0), one-sample t tests were used. (D) Percent change in retinal fluid at 4 weeks in individual patients. Statistical tests in this figure were 2-sided and adjusted for multiple comparisons with Holm-Bonferroni correction, n = 12.

Figure 2

Spectral domain-optical coherence tomography images of the same macular segmentation line at baseline and monthly follow-up visits in a patient naı¨ve to intravitreal anti-vascular endothelial growth factor (VEGF) therapy. There was a 59% reduction in retinal fluid at 1 month; retinal fluid completely resolved at the same macular segmentation line at month 2, and fluid remained stable up to month 3 without anti-VEGF injections. Collectively, all macular segmentation lines revealed a 92% total retinal fluid decrease at 3 months.

Figure 3

Changes in best-corrected visual acuity (BCVA) and reduction in anti-vascular endothelial growth factor injections during levodopa treatment in Cohort 2. (A) mean changes from baseline in BCVA ± SE in response to levodopa treatment. Starting from a baseline mean of 41 letters (20/40), BCVA increased by 4.4 letters at month 1, P = .06; and continued to improve through month 6, BCVA increased by 4.8 letters, P = .02; paired-sample t test. (B) Illustrates individual patient changes in BCVA at month 6, (C) shows individual patient percentage changes in retinal fluid at month 6, and (D) shows individual patient anti-VEGF injection rates prior to and during levodopa treatment; insets show mean injections per month ± SE. Overall, there was a 52% decrease in the rate of required intravitreal injections, compared with injection frequency prior to levodopa (P = .002; 95% CI, 16%−67%, paired-sample t test). Statistical tests in this figure were 2-sided and adjusted for multiple comparisons with Holm-Bonferroni correction, n = 11.